Helminthiasis is a widely occurring disease affecting animals, particularly warm-blooded animals, causing substantial economic losses. Particularly susceptible to the infections are sheep, cattle, goats, horses, and other domesticated herbivores. Many know anthelmintic agents have been discovered possessing varying degrees of efficacy on the particular helminths causing the infections. Certain classes of anthelmintics have a greater or lesser spectrum of activity, i.e., they are able to treat infections involving a wider or smaller range of parasites.
A particularly useful class of anthelmintics are those of the avermectin and milbemycin classes, exemplified by abamectin, ivermectin, doramectin, milbemycin D and moxidectin. These have activity against parasitic roundworms and also against some ectoparasites, but lack activity against cestodes and trematodes (flukes).
Liver fluke is a global disease which mainly infects cattle and sheep but can also develop in many other animals including horses, pigs, goats, rabbits and at least in Australia, native animals such as kangaroos and wombats. Humans may also be infected with liver fluke. Liver fluke can cause serious economic losses. Global losses due to liver fluke disease are estimated at over three billion U.S. dollars per year. In sheep, infection with liver fluke reduces production including wool growth and wool quality, lambing percentages and growth rates of lamb. Sheep can also die as a result of liver fluke infection.
Benzimidazoles, including triclabendazole, are well known for their anthelmintic activity. Triclabendazole is a particularly useful anthelmintic, having activity primarily vis a vis trematodes, and particularly against liver flukes. Triclabendazole is described in U.S. Pat. No. 4,197,307, and is also known as 5-chloro-6(2,3-dichlorophenoxy)-2-methylthio-1H-benzimidazole. Triclabendazole is highly effective against liver flukes at all stages of their life cycle, including early immature fluke, immature fluke and adult liver fluke.
A combination of anthelmintic actives, which would have the spectrum of activity of the avermectin/milbemycins and triclabendazole is desirable. However, successful combination formulations must provide for physical stability of the formulation for a commercially reasonable period of time; chemical stability of the actives therein; maintain or exceed the level of pharmacological activity of the individual actives, and be administrable to the animal in a suitable dosage form.
It is advantageous to have liquid formulations which contain the anthelmintic active(s) and which are easily administered to the animal by being poured on the backs of animals. Liquid formulations of therapeutic agents may be in the form of a solution or a suspension. Due to the highly insoluble nature of triclabendazole, it has been difficult to provide liquid formulations containing triclabendazole. As a result, anthelmintic formulations containing triclabendazole have usually been prepared as suspensions. However, suspension formulations have several disadvantages. By its very nature, the particulate matter in a suspension may settle or sediment to the bottom of the container upon standing. Such sedimentation may also lead to caking and solidification of the sediment with a resulting difficulty in redispersing the suspension upon agitation. The sedimentation causes further problems as it results in differences in the concentration of the active agent in the formulation. This is turn leads to difficulties in determining and obtaining the effective and safe dose for treatment of the animals. Suspensions are also less able to be absorbed when applied by way of pour-on administration.
For these reasons, it would be desirable to provide pour-on liquid formulations, which contain triclabendazole in the form of a solution, rather than in the form of a suspension. Solutions are sometimes required to obtain sufficient bioavailability. Solutions are liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents. However, substances in solutions are often more susceptible to chemical instability than those in the solid state.
When formulating anthelmintic compositions, it is necessary that the compositions maintain both the chemical activity of the active compounds, as well as the physical stability of the formulation. This allows for the compositions to be prepared well in advance of their intended use, and to also have a useful shelf life as a commercial product.
Furthermore, a suitable pour-on liquid formulation would preferably include solvents having the ability to effectively penetrate the skin, thereby making the anthelmintic active(s) more likely to be systemically absorbed by the animal. Preferably, a suitable pour-on formulation would have a low freezing point and low surface tension to help with administration as a pour-on, and would be highly water repellant to inhibit wash off from the animal during rain or other water exposure.